Researchers have long sought for a biochemical difference by which malignant cells could be distinguished from normal cells. The work of Warurg in the early part of the twentieth century (Warburg, The Metabolism of Tumors, Richard R. Smith & Co., New York, 1931) focused attention on the differences in the way that cancer cells metabolize glucose. Using a concept advanced by Pasteur, Warburg considered that cancer cells ferment while normal cells respire. The arguments advanced by Warburg (Annual Review of Biochemistry. 33:1, 1964) seemed to characterize the majority of rapidly growing malignant cells, and the occasional instance where the metabolism of the tumor does not strictly fit Warburg's criteria is limited to very slow growing cancers which do not produce death by cachexia and widespread metastasis.
However, some recent, knowledge with respect to the regulation of the energy metabolism in the cell was unknown to Warburg. For instance, the Crabtree effect (inhibition of respiration by glycolysis) is observed in practically all cells (Biochema et Biophysica Acta 591:209, 1980). The addition of glucose to anaerobic suspensions of glucose starved malignant cells causes a burst of respiration and glycolysis with lactate production which results in an inhibition of both respiration and glycolysis to values below those observed prior to the addition of glucose.
The rate limiting factor in glucose metabolism which determines the quantity of lactate formed in the cell has been shown to be dependent upon the rate at which glucose is transported across the cell membrane. This knowledge suggests that the biochemical defect in cancer cells does not reside in fermentation or respiration; but, rather, the primary defect must be the increased rate of glucose transport across the cell membrane. This must be related either to an enhancement of the transport mechanism or an actual increase in the receptor sites for glucose transport which are present in the membrane of the cell wall; and there is excellent substantiation for the latter explanation that a greater number of receptor sites are responsible.
The rate of glucose transport across cells has been shown to be directly related to the growth potential of the cell. Glucose is a requirement for energy needs related to synthesis, as well as for actual structural requirements in the synthesis of macromolecules (J Nat Can Inst. 62:3, January 1979). Because malignant cells exhibit an extensive augmentation of glucose transport, they are understandably much more sensitive to drugs which inhibit glucose transport than are normal cells. The magnitude of abnormal carbohydrate metabolism of malignant cells increases the competition for glucose which develops between rapidly growing tumors and the host's normal cells. Warburg mentions that the glycolysis of tumor cells can be so rapid as to reduce the blood sugar in diabetic patients. For example, the blood sugar concentration in rats with a rapidly growing sarcoma remains normal until the tumor/body weight ratio increases above 0.15. At ratios of 0.31 or greater, hypolglycemia occurs. Liver glycogen declines at high tumor/body weight ratios. Gluconeogenesis from lactate increases thirty fold over autogenous gluconeogenesis from endogenous alanine (Cancer Res. 40:1699, 1980). Similar findings have been made in patients with rapidly progressive malignant disease (Cancer Res. 39:1968, 1979; Cancer 33:66, 974). Obviously, cancers sequestrate glucose and glucose utilization in cancer patients is extremely high. The high potential for the malignant tumor to metabolize glucose has even caused it to be referred to as a glucose trap (Acta Chir Scan [Suppl] 498:141, 1980).
This excessive glucose turnover in malignant patients has again focused attention on the role of glucose metabolism in cancer cachexia. One consequence of the anaerobic metabolism of glucose is the release of lactate into the circulating blood. The lactic acid is transported to the liver by the circulating blood. The liver converts the lactic acid to glucose thus completing the Cori cycle. The conversion of lactate to glucose is energy consuming and has been estimated to account for 10% increase in energy expenditure (Cancer Res. 37:2336, 1977). The production of lactate may be so excessive in patients with cancer that with impairment of liver physiology as with extensive liver metastasis, lactic acidosis may occur (Cancer 47:2026, 1981). The severe carbohydrate drain causes excessive gluconeogenesis which further depletes the cancer patient (SA Med J. 59:518, 1981)(Ann NY Acad Sci, 72:103, 1980).
Glycogen synthesized from glucose is abundantly stored in cancer cells (Cancer 19:98, 1966); however, the glycogen content decreases during the exponential phase of tissue growth. Brain tumors for example contain five times as much glycogen as small mammal brains (J. Neurochem. 29:959, 1977). This further supports the concept that increased glucose transport is a significant requirement for the rapidly growing cancer cell. Slower growing tumors contain more glycogen than more rapidly growing tumors which utilize the glucose more swiftly (Can. Res. 41:1165, 1981). These factors support the concept that cancer cells transfer glucose more swiftly than do normal cells.
These energy related revelations have also turned attention to the glucose metabolism of growing cancer cells as a mechanism for the control of cancer growth. Lonidamine has been found to be a selective inhibitor of aerobic glycolysis in urine tumor cells (J Nat Can Ins. 66:497, 1981). Dactylirin is a new antibiotic which has a potential anticancer effect since it influences the energy yielding carbohydrate mechanisms which function in malignant cells (Can Res. 39:4242, October 1979).